Treatment of Lupus

This present application is a U.S. national stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2022/070860, filed Jul. 26, 2022, which claims priority to U.S. Provisional Application No. 63/225,974, filed Jul. 27, 2021, 2021, and to U.S. Provisional Application No. 63/254,663, filed Oct. 12, 2021, 2021, the entire contents of which are incorporated herein by reference in their entirety.

The instant application contains an electronic Sequence Listing that has been submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing was created on Jul. 18, 2022, is named “IFNAR-776-WO-PCT.xml” and is 22,443 bytes in size.

Systemic lupus erythematosus (SLE) is a chronic, multisystemic, disabling autoimmune rheumatic disease of unknown etiology. There is substantial unmet medical need in the treatment of SLE, particularly in subjects with moderate or severe disease. Long-term prognosis remains poor for many subjects.

A significant problem associated with the treatment of SLE, is the heterogeneous clinical manifestations of SLE. Any organ may be affected in SLE, with the skin, joints, and kidneys being the most commonly involved. Incomplete disease control leads to progressive organ damage, poor quality of life, and increased mortality, with approximately half of all patients with SLE developing organ damage within 10 years of diagnosis. There remains the need for a medical intervention that improves SLE disease activity across multiple systems.

Clinical manifestations of SLE include, but are not limited to, constitutional symptoms, alopecia, rashes, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, haemolytic anaemia, cognitive dysfunction and other nervous system involvement. Increased hospitalisations and side effects of medications including chronic oral corticosteroids (OCS) and other immunosuppressive treatments add to disease burden in SLE.

All of the therapies currently used for the treatment of SLE have well known adverse effect profiles and there is a medical need to identify new targeted therapies, particularly agents that may reduce the requirement for corticosteroids and cytotoxic agents. There has been only 1 new treatment (belimumab) for SLE approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the approximately 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE. However, belimumab is not approved everywhere, and the uptake has been modest. Many agents currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate mofetil/mycophenolic acid, have not been approved for the disease. Furthermore, these drugs all have well-documented safety issues and are not effective in all patients for all manifestations of lupus. Antimalarial agents (e.g. hydroxychloroquine) and corticosteroids may be used to control arthralgia, arthritis, and rashes. Other treatments include nonsteroidal anti-inflammatory drugs (NSAIDs); analgesics for fever, arthralgia, and arthritis; and topical sunscreens to minimize photosensitivity. It is often difficult to taper subjects with moderate or severe disease completely off corticosteroids, which cause long-term morbidity and may contribute to early cardiovascular mortality. Even small daily doses of 5 to 10 mg prednisone used long-term carry increased risks of side effects such as cataracts, osteoporosis, and coronary artery disease.

The clinical development of a new drug is a lengthy and costly process with low odds of success. For molecules that enter clinical development, less than 10% will eventually be approved by health regulatory authorities. Furthermore, the early clinical development of biotherapeutics is much lengthier than for small molecules.

Phase II trials are conducted in a small number of volunteers who have the disease of interest. They are designed to test safety, pharmacokinetics, and pharmacodynamics. A phase II trial may offer preliminary evidence of drug efficacy. However, the small number of participants and primary safety concerns within a phase II trial usually limit its power to establish efficacy. A Phase III trial is required to demonstrate the efficacy and safety of a clinical candidate. Critically, many clinical candidates that have shown promise at Phase II fail at Phase III. More than 90% of novel therapeutics entering Phase I trials fail during clinical development, primarily because of failure in efficacy or safety. The probability of success at phase III, following successful Phase II, is less than 50%.

The process of drug development is particularly difficult for SLE. This is because SLE is an especially complex and poorly understood disease. Not only is our understanding of the genetics of SLE rudimentary, but our insight into pathogenesis of most of the clinical manifestations are still relatively limited compared to other disease.

The complexity of SLE presents those wishing to develop new therapeutics with the problem of a patient population with extensive inhomogeneity. This makes protocol design for clinical trials in SLE even more difficult, for example, as regards to the choice of inclusion criteria and primary and secondary endpoints. It is further difficult to predict the disease course in each patient. This inevitably increases the background noise that reduces the statistical power of a trial. A high placebo response rate limits the range in which the tested new drug can show an efficacy signal, making clinical trials even more difficult to conduct and interpret.

The difficulty in developing effective therapeutics for SLE leads to an even higher failure rate of therapeutics in this area in clinical trials, compared to therapeutics for other indications. The development of novel therapeutics for the treatment of SLE has thus proved extremely difficult. There are many examples of clinical candidates that showed promise at Phase II but failed to show efficacy and/or safety in subsequent Phase or Phase III trials.

There remains an unmet clinical need in SLE particularly in patients resistant to conventional immunosuppressive therapies and immunomodulators. There is also a subset of SLE patients whose disease remains refractory to existing treatments (refractory disease, RD). Morbidity and mortality from active SLE remains high in such patients, and the search for safe and effective therapies to treat them is ongoing

Glucocorticoids remain the mainstay treatment for SLE with doses varying depending on severity of disease manifestation. There is no “safe” dose of oral glucocorticoids in relation to the risk for development of glucocorticoid-induced damage such as cataracts, osteoporosis and coronary artery disease, and whereas higher glucocorticoid-exposure has been shown to be associated with increased overall damage accrual, fairly low to moderate doses can also be related to increased damage.

Glucocorticoids are the most commonly used therapy for patients with SLE owing to their immunosuppressant and anti-inflammatory properties, which reduce disease activity and prevent flares. Up to 80% of patients with SLE are exposed to glucocorticoids, with the majority being treated long-term. Although it may provide short-term efficacy, the frequent or maintenance use of oral glucocorticoid therapy carries a significant burden of toxicity that can independently contribute to morbidity and mortality and can adversely affect health-related quality of life. Therefore, novel, effective, and long-term treatments for SLE are needed to both reduce overall disease activity and glucocorticoid use.

Anifrolumab (MEDI-546) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). It is composed of 2 identical light chains and 2 identical heavy chains, with an overall molecular weight of approximately 148 kDa. Anifrolumab inhibits binding of type I IFN to type I interferon receptor (IFNAR) and inhibits the biologic activity of all type I IFNs.

Type I interferons (IFNs) are cytokines that have been implicated in SLE pathogenesis based on the finding of increased IFN-stimulated gene expression in most patients with SLE. In the phase 3 TULIP-2 trial of anifrolumab in patients with moderate to severe SLE, treatment response (assessed using British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA]) was achieved by significantly more patients receiving anifrolumab compared with placebo at Week 5214. Similar results with this composite endpoint were observed in the phase 2 MUSE and phase 3 TULIP-1 trials 15.16

There is a huge unmet need for an SLE therapy with a better efficacy and safety profile the currently available therapies. As described above, a large number and broad range of different biologics have been proposed and subjected to clinical trials, but these trials have failed to meet clinical meaningful endpoints in pivotal studies. Initial promise at Phase II of many proposed therapeutics was not translated into significant and meaningful clinical effect in subsequent pivotal Phase III clinical trials. Furthermore, there is a need for an SLE therapy that is efficacious across multiple organ domains. Furthermore, even approved treats for SLE do not permit steroid tapering in many patients. There is further a subset of patients with refractory disease, i.e. having moderate to severe SLE despite treatment with standard therapies. Thus, there remains the need for safe and effective treatment of SLE that has proven clinical benefit, for example in a phase III double-blind, randomized, placebo controlled trial.

The present invention solves one or more of the above-mentioned problems.

The present invention relates to a method of treating systemic lupus erythematous (SLE) in a subject in need thereof, the method comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject before treatment with the IFNAR1 inhibitor, and wherein the subject has received prior treatment with one or more immunomodulators before administration of the IFNAR1 inhibitor.

The invention also relates to a method of identifying a subject as suitable for treatment with an IFNAR1 inhibitor, the method comprising identifying the subject as having received prior treatment with one or more immunomodulators before administration of the IFNAR1 inhibitor, and administering the IFNAR1 inhibitor to the subject.

The invention also relates to a method of treating SLE in a subject in need thereof, the method comprising administering a IFNAR1 inhibitor to the subject, wherein the method reduces SLE activity in the subject compared to the SLE activity in the subject before treatment with the IFNAR1 inhibitor, and wherein the subject has severe, established and/or refractory SLE.

The invention is supported inter alia by data, presented herein for the first time, from two phase III, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials (NCT02446899 and NCT02962960) demonstrating that an IFNAR1 inhibitor (anifrolumab) treats SLE in patients that have been previously treated with one or more immunomodulator biologics, wherein the SLE disease in the subject has not been controlled. Treatment with anifrolumab is more effective in these patients than in biologic naïve patients. The invention is also supported by data, presented herein for the first time, demonstrating that an IFNAR1 inhibitor treats SLE in subjects who have moderate to severe SLE despite standard therapy (i.e. refractory disease).

Baseline demographics, disease characteristics, and non-biologic SLE treatments were generally similar between groups.

: Forest plot of efficacy endpoints in the biologic-experienced and biologic-naïve patients with SLE in data pooled from the TULIP-1 and TULIP-2 trials

Anifrolumab was associated with greater treatment differences over placebo (Δ) in biologic-experienced vs biologic-naïve patients across endpoints, including BICLA response (Δ=19.4 vs Δ=16.6), SRI(4) response (Δ=25.3 vs Δ=9.1), and oral GC tapers (Δ=24.7 vs Δ=17.5).

: BICLA response rate at Week 52 by previous use of abatacept, stratified Cochran-Mantel-Haenszel approach

: Previous use of abatacept.: No previous use of abatacept. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of belimumab, stratified Cochran-Mantel-Haenszel approach

: Previous use of BELIMUMAB.: No previous use of belimumab. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of epratuzumab, stratified Cochran-Mantel-Haenszel approach

: Previous use of epratuzumab.: No previous use of epratuzumab. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of rituximab, stratified Cochran-Mantel-Haenszel approach

: Previous use of rituximab.: No previous use of rituximab. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of sifalimumab, stratified Cochran-Mantel-Haenszel approach

: Previous use of sifalimumab.: No previous use of sifalimumab. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of tabalumab, stratified Cochran-Mantel-Haenszel approach

: Previous use of tabalumab.: No previous use of tabalumab. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1.

: BICLA response rate at Week 52 by previous use of TNF inhibitors, stratified Cochran-Mantel-Haenszel approach

: Previous use of TNF inhibitors.: No previous use of TNF inhibitors. Baseline is defined as the last measurement prior to randomization and investigational product does administration on Day 1. Phase III pool includes study 04 (D3461C00004) and study 05 (D3461C00005) (excluding the 150 mg group from study 05). BICLA response is defined as reduction of all baseline BILAG-2004 A and B scores and no worsening in other organ systems, no worsening from baseline in SLEDAI-2K, and no increase in >=0.030 points on a 3 point PGA VAS from baseline. Subjects treated with restricted medication beyond protocol allowed threshold, and those who discontinued investigational product (anifrolumab), are regarded as non-responders. The responder/non-responder rates (percentages, the difference in estimates and associated 95% CI are calculated using a stratified CMH approach, with stratification factors SLEDAI-2K score at screening, Day 1 OCS dose and type I IFN gene signature test result at screening. In the pooled analysis an additional stratification factor is added for study (study 04 vs study 05). The nominal p-values presented are based on this CMH model. Previous use: the end date of therapy is prior to investigational product dose administration on Day 1. TNF inhibitors are identified using preferred terms: adalimumab, etanercept, infliximab.

: Safety in biologic-experienced and biologic-naïve patients with SLE in data pooled from the TULIP-1 and TULIP-2 trials

Incidence of serious adverse events was higher in biologic-experienced vs biologic-naïve patients with anifrolumab and placebo.

: Mean anifrolumab serum concentration-time profiles

: Study MI-CP180 in SSc—Mean anifrolumab serum concentration-time profiles following a single IV dose. Data represent+/−SD. Mean data below LLOQ are not plotted. IV, intravenous; LLOQ, lower limit of quantification; MEDI 546, anifrolumab; n, number of patients in a subgroup; SSc, systemic sclerosis.: Study 06 in healthy volunteers-Mean anifrolumab serum concentration-time profiles following a single SC and IV dose. Samples with actual collection time deviating from nominal collection time by >10% were excluded from the mean. IV, intravenous; N, number of subjects; SC, subcutaneous.

: Study 08 study design and results

: Study design for phase II of SC anifrolumab in SLE patients. Study 08 (NCT02962960) evaluated the effect of two anifrolumab doses every other week.: Mean serum concentration of anifrolumab over time.: Anifrolumab neutralization of the type I IFN gene signature

: Computed median AUC Ratios (SC/IV)

: Computed median AUC Ratio (SC/IV) between weeks 0-52 for various SC doses. The computed median AUC Ratio (SC/IV), based on the estimated bioavailability from Study 06, between weeks 0-52, where the subcutaneous dose is either 75 mg (+sign), 90 mg (empty squares), 105 mg (circles), 120 mg (triangles), or 135 mg (filled squares). The subcutaneous dose here is administered once every 7 days (QW); the IV dose is administered once every 4 weeks (Q4W) at a dose of 300 mg. Based on the AUC, both 90 and 105 mg SC QW appear similar to 300 mg IV.: Computed median AUC ratio (SC/IV) for 90 mg and 105 mg SC QW. The computed median AUC Ratio (SC/IV), based on the estimated bioavailability ˜7% lower than the bioavailability calculated from Study 06, between weeks 0-52, where the subcutaneous dose is either 90 mg SC QW or 105 mg SC.

: Anifrolumab concentration over time at different doses

: A plot showing (computed) trough concentrations of plasma anifrolumab in a patient administered either (i) 105 mg of anifrolumab subcutaneously, once every 7 days (straight line); (ii) 300 mg anifrolumab intravenously, once every 4 weeks (lower dotted line); (ii) 1000 mg anifrolumab intravenously, once every 4 weeks (upper dotted line). Shaded area represents the area between 5th and 95th percentiles of the 300 mg IV Q4W dose.: Anifrolumab trough concentration in IFNGS high SLE subjects. Computed trough concentrations of anifrolumab in IFNGS high patients plasma after administration as follows: (i) 300 mg IV Q4W; (ii) 90 mg SC QW; (iii) 105 mg SC QW; (iv) 135 mg SC QW; (v) 1000 mg IV Q4W. SC=subcutaneous. Based on trough, both 90 and 105 mg SC QW were projected to have higher PD suppressions than 300 mg IV.

: Positive Exposure-BICLA relationship observed in TULIP 1 & TULIP 2 in IFNGS high patients